Diphasic injection composition containing dispersed and continuous phases useful for reparative and plastic surgery

ABSTRACT

Biocompatible diphasic compositions are prepared comprising a dispersed phase suspended in a continuous phase, more particularly suitable for use as a filling material in reparative and plastic surgery. The dispersed phase consists of particles of at least one hydrogel of a (co)polymer obtained by polymerizing and cross-linking acrylic acid, methacrylic acid and/or at least one derivative of said acids. The continuous phase is an aqueous solution or hydrogel of a polymer selected from proteins, polysaccharides and their derivatives which have been cross-linked. The polysaccharide may be hyaluronic acid, its salts and a mixture of its salts, advantageously consisting of a sodium hyaluronate.

The present invention has for its principal object diphasic injectablecompositions, in particular useful in reparative and plastic surgery. Ithas more precisely for object:

biocompatible diphasic compositions comprising a dispersed phase insuspension in a continuous phase;

a method for preparing said compositions;

a filling material useful in reparative surgery and in plastic surgery,based on said diphasic compositions.

The present invention proposes in particular a satisfactory solution tothe technical problem of durable filling of the defects of volume of theskin, such as wrinkles or scars, particularly on the face.

With reference to this technical problem, different approaches and inparticular different diphasic injection compositions have already beenproposed according to the prior art.

As from 1970, Jaime Planas had the idea to make particles of silicone,in order to inject them under the skin.

More precisely, it has been described:

in EP-A-0 406 375: an alloplastic implant based on a histocompatiblesolid: said pulverulent solid being constituted by solid particles ofdiameter included on average between 10 μm and 200 μm, and which presenta smooth surface having no angle nor edge. A product which correspondsto this Patent Application is found at present on the market. Saidproduct, marketed under the Trademark Artecoll®, consists ofmicrospheres of polymethacrylate (PMMA) in suspension in a collagensolution;

in EP-A-0 466 300: a viscoelastic gel comprising a gelatinous phase(having undergone a low-rate cross-linking) dispersed in a liquid phase(not having undergone cross-linking); said two phases advantageouslyhaving been prepared from fibers of Hylan (natural hyaluronic acidchemically modified in situ for the purpose of facilitating extractionthereof from the tissues);

in U.S. Pat. No. 5,137,875: injectable solutions or dispersions ofcollagen, containing hyaluronic acid in solution;

in WO-A-96 33751: diphasic compositions capable of containing in theircontinuous and dispersed phases hyaluronic acid or one of its salts;said acid or salt intervening, “relatively” cross-linked in the form offragments, in order to constitute the dispersed phase, and in aqueoussolution, not or very little cross-linked, in order to constitute thecontinuous phase. It is provided to employ in said continuous phase, incombination or in place of said hyaluronic acid or one of its salts,another biocompatible polymer selected from proteins, polysaccharidesand derivatives thereof.

Furthermore, a product, of the diphasic composition type, would beevaluated in the United States. It is principally constituted bysilicone balls, dispersed in a solution of polyvinylpyrrolidone.

Incidentally, it will be noted here that documents EP-A-826 381, FR-A-2568 127, U.S. Pat. No. 4,657,553 and U.S. Pat. No. 4,563,490 do notdescribe diphasic compositions.

There are therefore numerous variants of diphasic compositions, usefulin reparative and plastic surgery and it does not appear obvious todevelop one of them, optimalized with reference to the numerousparameters consisting of:

the exact nature and form of the continuous phase;

the nature, form, surface state . . . of the dispersed phase.

In such a context, Applicants propose a novel type of diphasiccomposition which shows particularly high-performance.

The biocompatible diphasic composition of the type of the inventiontherefore includes a dispersed phase suspended in a continuous phaseand, characteristically, said dispersed phase consists of particles ofat least one hydrogel of a (co)polymer obtained by polymerizing andcross-linking acrylic acid and/or methacrylic acid and/or at least onederivative of said acids.

The diphasic compositions of the invention are injectable compositions.They have been formulated with this in view. It is particularly for thatpurpose that they contain a continuous phase; said phase serving asinjection vehicle for the particles of the dispersed phase.

The term injectable used in the present text means manually injectableby means of syringes provided with conventional needles. The diphasiccompositions of the invention are particularly interesting in that theycan be formulated to be injectable by means of very fine needles (with adiameter included between 0.3 and 0.5 mm). The person skilled in the artunderstands that the determining parameter is that of the largestdimension of the particles in suspension. Within the framework of thepresent invention, it is in particular possible to formulatecompositions injectable through hypodermic needles of 30 G ½, 27 G ½, 26G ½, 25 G. Said compositions constitute the most advantageous variant ofthe compositions of the invention.

The injectable diphasic compositions of the invention are moreparticularly intended for dermic injection (superficial, mean or deep)for an implantation in the dermis. To that end, for the purpose ofeliminating any unpleasant feeling or any pain during their injectionand during their implantation, they are advantageously buffered at a pHincluded between 6.5 and 7.5, preferably included between 7 and 7.4, andpreferably still, between 7.2 and 7.3.

In this way, the two continuous and dispersed phases of said diphasiccompositions are advantageously buffered at that pH.

A phosphate buffer is generally employed.

The diphasic compositions of the invention therefore comprise anoriginal dispersed phase as specified hereinabove, suspended in anadequate continuous phase.

Said continuous phase must, in effect, be capable of performing severalfunctions, and in particular:

a) it must maintain the dispersed phase in suspension, in stable manner,

b) it must constitute a high-performance injection vehicle,

c) after injection and implantation of the diphasic composition, it mustadvantageously protect said dispersed phase (in particular prevent itfrom migrating and promote the formation of fibroblasts around itsparticles, which slows down degradation thereof).

With reference to points a and b, it will be understood that acompromise must be adopted. Said continuous phase must be sufficientlyfluid to be able to be easily injected, and sufficiently viscous toavoid decantation of the dispersed phase.

The compromise mentioned hereinbefore may be obtained with differenttypes of continuous phase. Within the framework of the invention,certain types, specified hereinafter, are largely preferred.

We now propose to give precisions on each of the phases—continuousphase, dispersed phase—of the diphasic compositions of the invention.

By way of continuous phase, an aqueous solution of at least one polymerselected from proteins, polysaccharides and their derivatives,cross-linked or not, is advantageously employed. Said polymer, dependingon its nature, in order to perform the above-recalled functions, iscapable of intervening not cross-linked, slightly cross-linked orstrongly cross-linked. Collagen, albumin, elastin . . . may inparticular be employed as protein; as polysaccharide or derivative ofpolysaccharide:hyaluronic acid, its salts, sulphates of chondroitine,keratane, heparin, alginic acid, starch, carboxymethylcellulose,chitosane.

The possible cross-linking of this type of polymer does not raiseparticular difficulties for the person skilled in the art.

It is more particularly recommended to employ “an aqueous solution” of apolymer selected from hyaluronic acid, its salts and mixtures of itssalts; said polymer advantageously being cross-linked. In fact,according to a preferred variant, said continuous phase of the diphasiccompositions of the invention is a hydrogel of a cross-linked polymerselected from hyaluronic acid, its salts and mixtures of its salts; saidcross-linked polymer advantageously consisting of a sodium hyaluronate.

The term hyaluronic acid is used in the following text as generic nameto designate both hyaluronic acid per se and its salts or mixtures ofsalts and in particular salts of hyaluronate. The diphasic compositionsof the invention advantageously contain sodium hyaluronate in theircontinuous phase, by way of polymer selected from hyaluronic acid, itssalts and mixtures of its salts. It is already specified that saidsodium hyaluronate employed is advantageously of bacterial origin.

Said hyaluronic acid (or at least one of its salts) has been moreespecially retained in view of its advantageous properties. It may inparticular be obtained by the bacterial route, by cellular route(therefore bereft of any contaminant of virus type or prions). Itpresents both a strong gelatinous nature, a noteworthy lubricatingpower, a good biocompatibility and a good hold in the organism.Moreover, it is easily cross-linkable.

Cross-linked, it is capable of presenting the viscosity required withinthe context of the invention and, in any case, it is more resistant todegradation and to heat (the latter point is not negligible insofar asthe compositions of the invention are generally sterilized in anautoclave).

Characteristically, the continuous phase of the compositions of theinvention is advantageously based on cross-linked hyaluronic acid. It isno longer really question of an aqueous solution but of a hydrogel. Saidhyaluronic acid has been conventionally cross-linked with the aid of atleast one cross-linking agent. In order to obtain a hydrogel containinga reasonable quantity of said cross-linking agent, it is recommended touse as starting material a hyaluronic acid whose molecular mass isgreater than or equal to 1 million Daltons. According to an advantageousvariant, it is recommended to use a hyaluronic acid whose molecular massis included between 2 and 4 million Daltons. Furthermore, it isrecommended to carry out said cross-linking via the hydroxy functions ofthe hyaluronic acid, by means of a cross-linking agent (at least one),under conditions which lead to a cross-linking rate of said hyaluronicacid (starting material) characterized by the ratio: total number ofreactive functions of said cross-linking agent/total number ofdisaccharide repeating units of the molecules of hyaluronic acidpresent, included between 0.25 and 0.50.

In fact, the network of the hydrogel, which thus constitutes thecontinuous phase of the diphasic compositions of the invention, is basedon molecules of hyaluronic acid joined by bridges of molecules ofcross-linking agent; each of the disaccharide repeating units of saidmolecules of hyaluronic acid advantageously having between 0.25 and 0.50of its hydroxy functions engaged in such bridges.

By way of cross-linking agent, any agent known for cross-linking thehyaluronic acid via its hydroxy functions—at least bifunctionalcross-linking agent—and in particular a polyepoxide or its derivatives,may be employed. By way of such cross-linking agent, the following mayin particular by employed: epichlorhydrin, divinylsulfone,1,4-bis-(2,3-epoxypropoxy)butane (or 1,4-bis(glycidyloxy)butane or1,4-butanediol diglycidyl ether=BDDE),1,2-bis-(2,3-epoxypropoxy)ethylene, 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane . . . It is not excluded from the scope of the invention toemploy a plurality of cross-linking agents . . . It is more particularlyrecommended to employ 1,4-butanediol diglycidyl ether (BDDE).

The person skilled in the art knows, in any case, how to master thecross-linking of hyaluronic acid.

The hydrogel constituting the continuous phase of the diphasiccompositions of the invention, based on cross-linked hyaluronic acid,advantageously contains said cross-linked hyaluronic acid at aconcentration included between 10 and 25 mg/g, advantageously between 15and 25 mg/g. It may be specified here, in non-limiting manner, that saidhydrogel in fact generally contains more than 95% by weight of water . ..

Incidentally, it is recalled here that the hyaluronic acid, from whichthe hydrogel constituting the continuous phase of the diphasiccompositions of the invention is preferably elaborated, isadvantageously obtained by the bacterial route (rather than byextraction from animal tissues, cockscomb and umbilical cords inparticular . . . ) and that it is more particularly recommended to use asodium hyaluronate. In fact, for elaborating said hydrogel theintervention of fibers of sodium hyaluronate, obtained by the bacterialroute, is more particularly recommended.

The dispersed phase consists of particles of at least one hydrogel of a(co)polymer obtained by polymerizing and cross-linking acrylic acidand/or methacrylic acid and/or at least one derivative of said acids.

The size of said particles is conventionally more or less defined,insofar as:

they must not be too small: in such a hypothesis, they would be rapidlyeliminated by the giant cells or the macrophages, they would migrate tooeasily and might thus develop a carcinogenic effect, and

neither must they be too voluminous: in such a hypothesis, difficultieswould be encountered in injecting them through hypodermic needles (suchas needles 30 G ½ which present an internal diameter of 160 μm) and itis possible that they would not suit for filling wrinkles of small size. . . It will be noted here that, concerning the maximum size of saidparticles, their deformability which is more reduced in view of thematerial constituting them, than that of particles of other types, willbe taken into account.

The largest dimension of said particles is generally included between 10and 120 μm, advantageously between 20 and 80 μm.

One speaks of the largest dimension of said particles (i.e. of theirequivalent diameter) insofar as it is advantageously question offragments of hydrogel which present a rough surface, fragments ofhydrogel generally obtained by crushing a mass of hydrogel.

It is in no way expressly excluded from the scope of the invention toemploy particles with symmetry of revolution, presenting a smoothsurface, bereft of angle and edge, but it is preferred by far to employfragments such as specified hereinabove, fragments that may be obtainedeasily and which, a priori, present two advantages:

a smooth implant surface has greater risks of provoking the formation oftumours than a rough surface (Prog. Exp. Tumor Res., Vol. 5, pages85-133: “Carcinogenesis through solid state surfaces” by F. BISCHOFF andG. BRYSON);

a granulous particle surface promotes the growth of the fibrous tissuesaround, thus fixing the particles on the site of injection and avoidingtheir migration (Cosmetics, Vol. 100, No. 6, pages 1570-1574:“Bioplastique at 6 years”, by ERSEK R. A., GREGORY S. R. and SALISBURYM. D.).

The fragments constituting the dispersed phase of the compositions ofthe invention may in fact present totally random shapes and inparticular oval, rounded, triangular, square geometries . . . and eventhe form of sticks.

Said particles are particles of hydrogel. In that, they are inparticular less traumatizing than particles of PMMA type of the priorart.

Said particles generally present, at equilibrium, a water contentincluded between 10 and 40% by weight, advantageously close to 25% byweight.

Said hydrogel is a hydrogel of a methacrylic and/or acrylic,cross-linked, hydrophilic polymer or copolymer. It is obtained bypolymerizing and cross-linking at least one monomer selected fromacrylic acid, methacrylic acid and their derivatives.

Said hydrogel is advantageously obtained from at least one monomerselected from

acrylic acid methacrylic acid ethyl acrylate methyl methacrylate (MMA)propyl acrylate ethyl methacrylate (EMA) n-butyl acrylate propylmethacrylate isobutyl acrylate n-butyl methacrylate hexyl acrylateisobutyl methacrylate octyl acrylate hexyl methacrylate n-decyl acrylateoctyl methacrylate dodecyl acrylate n-decyl methacrylate hydroxyethylmethacrylate (HEMA) dodecyl methacrylate hydroxypropyl methacrylatehydroxybutyl methacrylate hydroxyisobutyl methacrylate hydroxyhexylmethacrylate hydroxyoctyl methacrylate hydroxy-n-decyl methacrylatehydroxydodecyl methacrylate.

It will obviously be understood that, insofar as said (meth)acrylic(co)polymer must be hydrophilic (in order to constitute said hydrogel),it is excluded that it be question of a methyl polymethacrylate (PMMA).When said methyl methacrylate (MMA) intervenes, it forcibly intervenesby way of comonomer.

The (meth)acrylic hydrophilic (co)polymer constituting the particles ofthe dispersed phase of the diphasic compositions of the invention,advantageously consists of cross-linked hydroxyethyl polymethacrylate(PHEMA) or, even more advantageously, of a cross-linked copolymer:

of hydroxyethyl methacrylate (HEMA) and

of ethyl methacrylate (EMA).

Said hydroxyethyl methacrylate (HEMA) gives the particles of thedispersed phase hydrophily and suppleness while said ethyl methacrylate(EMA) optimalizes their mechanical properties. The quantity ofintervention of said EMA must obvously remain within reasonable limitsin order not to compromise the hydrophilic nature of the copolymer. Itis specified here that said copolymer is advantageously obtained bycopolymerization, for 100 parts by weight of monomers: HEMA+EMA, of 77.5to 87.5 parts by weight (advantageously from 80 to 85 parts by weight)of HEMA and 12.5 to 22.5 parts by weight (advantageously from 15 to 20parts by weight) of EMA. According to a particularly advantageousvariant, it is obtained by copolymerization of 82.5 parts by weight ofHEMA and 17.5 parts by weight of EMA.

In this way, the methacrylic copolymer which constitutes the particlesof the dispersed phase of the diphasic compositions of the inventioncontain repeating units [HEMA] and repeating units [EMA] in a ratioR:R=[HEMA]/[HEMA], generally included between 3.0 and 6.1,advantageously included between 3.5 and 5 and, according to a preferredvariant, being 4.1.

Said poly[HEMA/EMA] copolymer is, as specified hereinabove,cross-linked. Such a cross-linking is indispensable to ensure cohesionof the material and its stability. An (at least one) cross-linkingagent—bifunctional—must therefore intervene, in an efficient quantity,during copolymerization of the HEMA and EMA monomers. This efficientquantity—generally, at maximum, some parts by weight: in principleincluded between 0.5 and 5 parts by weight, advantageously includedbetween 0.5 and 2 parts by weight, for 100 parts by weight of HEMA+EMAmonomers—must obviously remain reasonable. It is not a question of theintervening cross-linking agent constituting a comonomer andconsequently modifying the properties, particularly the mechanical ones,of the poly(HEMA/EMA) copolymer.

In any case, the person skilled in the art is not unaware that theincrease in the rate of intervening cross-linking agent reduces thewater content of the hydrogels and increases their vitreous transitiontemperature.

It is indicated here that said cross-linking agent intervenes in thestructure of the copolymer, generally in such a quantity that the ratio:$R^{\prime} = \frac{\begin{matrix}\text{total~~number~~of~~reactive~~functions~~of~~said} \\\text{cross-linking~~agent~~present~~~~}\end{matrix}}{\begin{matrix}\text{total~~number~~of~~reactive~~functions~~(methacrylates)~~of~~the} \\\text{reagents~~present~~(HEMA,~~EMA)}\end{matrix}}$

is included between 6.10⁻³ and 60.10⁻³. Said ratio R′ is advantageously10⁻².

Concerning the reactive functions of said cross-linking agent, it isadvantageously question of acrylate and/or methacrylate functions. Theperson skilled in the art knows numerous cross-linking agents performingsuch functions, and in particular:

butanediol dimethacrylate and diacrylate

hexanediol dimethacrylate and diacrylate

decanediol dimethacrylate and diacrylate

ethylene glycol dimethacrylate (EDMA)

tetraethylene glycol dimethacrylate.

Within the scope of the present invention, the intervention of thecross-linking agents listed hereinabove and more particularly that ofEDMA, is recommended in non-limiting manner.

Thus, the poly(HEMA/EMA) copolymer constituting the particles of thedispersed phase of the diphasic compositions of the invention iscross-linked by cross-linking agents of this type (or of an equivalenttype) of which trace is obviously found in its skeleton.

Said poly(HEMA/EMA) copolymer is prepared in manner known per se, bycopolymerizing a mixture of HEMA and EMA monomers in the presence ofefficient quantities of at least one polymerization initiator and atleast one cross-linking agent.

It has been seen hereinabove that, concerning the cross-linking agent,an efficient quantity (generally from 0.5 to 5 parts by weight andadvantageously from 0.5 to 2 parts by weight, for 100 parts by weight ofmonomers: HEMA+EMA), of a cross-linking agent such as EDMA, intervenes.Said EDMA may intervene in particular at the rate of 0.8 part by weight.Other cross-linking agents as indicated hereinabove, may intervene inplace of said EDMA.

By way of initiator of the radical HEMA-EMA copolymerization, thefollowing may in particular be used:

a mixture of sodium phosphite and sodium phosphate (or any otheroxidoreduction couple);

an azo compound such as azobisisobutyronitrile (AIBN) or (2,2′-azobis(2,4-dimethyl valeronitrile)(AIVN), in particular marketed by WAKO underreference V65, of which the developed formulae are reproducedhereinbelow:

This latter compound is particularly preferred in view of its lowtoxicity, as well as that of its products of degradation. (However, itwill be generally noted that said polymerization initiator intervenes ina very small quantity and is generally eliminated at the end of themethod for preparing the hydrogel);

a peroxide such as benzoyl peroxide.

The person skilled in the art knows how to master the quantity ofintervention of said radical polymerization initiator (generally lessthan 1 part by weight for 100 parts by weight of monomers: HEMA+EMA)and, in general. the kinetics of polymerization of the reactionalmixture. In particular, he knows that, as oxygen neutralizes the actionof said polymerization initiator, it is highly preferable to eliminateit from the reactional mixture before the rise in temperature. Abubbling-through of inert gas of said reactional mixture is highlyrecommended. Concerning the heating programme, its optimalization iswithin the scope of the person skilled in the art.

Said cross-linked poly(HEMA+EMA) copolymer is therefore largelyrecommended by way of material constituting the particles of thedispersed phase of the diphasic compositions of the invention.

The precisions given hereinabove with reference to the preparation ofsaid copolymer, particularly those relative to the nature of thecross-linking agent(s) and polymerization initiator(s) likely tointervene, are obviously applicable to the context of the(co)polymerization and cross-linking of monomers of other natures forthe preparation of other polymers or copolymers suitable forconstituting the particles of the dispersed phase.

Within the diphasic compositions of the invention. the particles of thedispersed phase generally intervene at a rate of 10 to 30% by mass,advantageously at a rate of 15 to 25% by mass. Generally, one has:${10\quad \%}\quad \leq \frac{{mass}\quad {of}\quad {the}\quad {dispersed}{\quad \quad}{phase}}{\begin{matrix}{{{mass}\quad {of}\quad {the}\quad {dispersed}\quad {phase}} +} \\{{mass}\quad {of}\quad {the}\quad {continuous}\quad {phase}}\end{matrix}} \leq {30\quad {\%.}}$

The continuous phase is considered hydrated, while the dispersed phasemay be considered dry or at equilibrium. Advantageously, in this type ofratio, the dry mass of the dispersed phase, i.e. the dry mass of theparticles, is considered.

It is specified here that a single type of particles generallyintervenes within the dispersed phase. However, it is in no way excludedfrom the scope of the invention to employ particles of different shapeand/or nature . . . , conjointly.

Concerning the preparation of the diphasic compositions of theinvention, the person skilled in the art has already understood that itdoes not raise particular difficulties. Said preparation, whichconstitutes the second object of the present invention, comprises:

the preparation of the continuous phase (advantageously that of ahydrogel of cross-linked hyaluronic acid);

the preparation of the dispersed phase (particles of at least onehydrogel of a (co)polymer obtained by polymerizing and cross-linkingacrylic acid and/or methacrylic acid and/or at least one derivative ofsaid acids);

the incorporation and the mixture in said continuous phase of saiddispersed phase.

The preparation of the continuous phase and in particular that of ahydrogel of cross-linked hyaluronic acid, advantageously at the rate ofcross-linking and at the concentration of acid specified hereinabove,does not raise any particular difficulty.

Similarly, the particles of the dispersed phase may be obtained by anymethod known per se. Particles with symmetry of revolution, with smoothsurface, and in particular microspheres, may be obtained byemulsification.

It has been seen that it was recommended to prepare fragments with roughsurface; said fragments being advantageously obtained by mechanicallycrushing an appropriate mass of hydrogel.

Within the framework of the method of the invention, it isadvantageously recommended to prepare the particles of the dispersedphase, to dry them and to add them, dried, to the continuous phase.

The prepared diphasic composition is advantageously sterilized forstorage. It is recommended to pack it, before sterilization and storage.It is advantageously packed in syringes. It is in that case ready foruse.

In accordance with its final object, the invention therefore relates toa filling material, useful in reparative surgery and in plastic surgery,based on the diphasic compositions such as described hereinabove.

Said material is particularly high-performance, in particular in termsof stability and non-traumatizing nature, due to the nature andconsistency of its continuous phase (advantageously cross-linked HA) anddispersed phase (hydrogel).

The use of such a filling material is recommended for filling inparticular wrinkles of the face such as the glabellar wrinkle, theperi-buccal wrinkles, the naso-genial furrows, for attenuating crowsfeet. . .

The invention is illustrated by the following example.

A diphasic composition of the invention was prepared from fibers ofsodium hyaluronate (NaHa) for the continuous phase and from fragments ofa poly[HEMA/EMA] hydrogel for the dispersed phase.

a) Preparation of the Continuous Phase

Said continuous phase is prepared with fibers of sodium hyaluronate (ofmolecular mass: M_(w)≈2.9 10⁶ Da), of bacterial origin. An 11.5% by masssolution of said fibers in 0.25 M sodium hydroxide is firstly prepared.

To said homogenized solution. 60 μl of 1,4-butanediol diglycidyl ether(BDDE) are added. The mixture obtained, homogenized, is placed in awater bath at 50° C. for 2 hours.

The resultant gel is then neutralized by the addition of 1M hydrochloricacid, then diluted by phosphate buffer at pH 7.2 until a concentrationof NaHa of 20 mg/g is obtained.

This gel is then purified by dialysis in a phosphate buffer bath inorder to eliminate from its structure both the cross-linking agent(BDDE) and the polymer which have not reacted.

Within such a gel, the ratio: total number of reactive functions of saidcross-linking agent/total number of disaccharide repeating units of themolecules of the polymer present, is 0.27.

b) Preparation of the Dispersed Phase

Discs or sticks of an acrylic hydrogel were prepared in a first step, asfollows:

82.5 g of hydroxyethyl methacrylate (HEMA), 17.5 g of ethyl methacrylate(EMA), 1 g of 4-methacryloxy-2-hydroxybenzophenone (MOBP), 0.8 g ofethylene glycol dimethacrylate (EDMA) and 0.2 g of benzoyl peroxide,were poured in a beaker.

The reactional mixture was homogenized then argon was bubbled throughfor 2 mins. The solution thus deoxygenated was then distributed inmoulds; said moulds were then placed:

48 hours in a water bath at 40° C.;

48 hours in a water bath at 60°:

then 48 hours in an oven at 100° C.

The material obtained, after cooling, was demoulded.

The demoulded discs or sticks were then mechanically crushed. The powderthus obtained was successively sieved over sieves of mesh 100, 40 and 25μm. Only the fragments recovered on the 25 μm sieve were kept. They werethen purified in an ebullient alcohol/water bath, left to decant inorder to eliminate the small fragments possibly remaining on the 25 μmsieve, and finally rinsed in two successive baths of deionized water.After drying, under flux (class 100), of the fragments thus obtained,they were again sieved over 25 μm, before being used for the finalproduct.

c) Preparation of the Diphasic Composition

11 g of dry fragments, as obtained in point b), are added to thecross-linked gel of NaHa, as obtained in point a). The whole is mixed inorder to obtain a homogeneous dispersion. The mass ratio m=mass of thefragments/(mass of the fragments+gel mass), is 0.2.

Samples of said diphasic composition obtained were in particularsubjected to tests of extrudability, with a view to characterizing theforce necessary for its injection. Said tests were carried out with theaid of a VERSATEST (MECMESIN) traction apparatus.

For a speed of compression of 12.5 mm/min., the characteristic force ofthe injection through:

a needle of30 G ½ is 25 to 30 N,

a needle of27 G ½ is 12 to 15 N.

d) Packing of the Diphasic Composition

The dispersion or suspension obtained is placed in syringes which aresterilized in an autoclave. Said dispersion is injectable, in particularthrough needles of 25 G to 30 G ½.

What is claimed is:
 1. A biocompatible diphasic composition comprising adispersed phase and a continuous phase, said dispersed phase residing insuspension in said continuous phase, wherein said dispersed phaseconsists of particles of at least one hydrogel of a polymer/copolymerobtained by polymerizing and cross-linking acrylic acid, methacrylicacid and/or at least one derivative of said acids; and wherein saidcontinuous phase is an aqueous solution or hydrogel of at least onepolymer selected from proteins, polysaccharides and their derivatives,which has been cross-linked.
 2. The composition according to claim 1,wherein said continuous phase is a hydrogel of a cross-linkedpolysaccharide selected from hyaluronic acid, its salts and mixtures ofits salts.
 3. The composition according to claim 1, wherein saidcontinuous phase is a hydrogel of cross-linked polysaccharide which issodium hyaluronate.
 4. The composition according to claim 2, wherein thehydrogel constituting said continuous phase is obtained from saidpolysaccharide whose molecular mass is greater than or equal to 1million Daltons, which was cross-linked, via its hydroxy functions, bymeans of a cross-linking agent, at a cross-linking rate defined by theratio: total number of reactive functions of said cross-linkingagent/total number of disaccharide repeating units of the molecules ofsaid polysaccharide, wherein said ratio is between 0.25 and 0.50.
 5. Thecomposition according to claim 4, wherein said polysaccharide hasmolecular mass ranging between 2 and 4 million Daltons.
 6. Thecomposition according to claim 2, wherein the hydrogel constituting saidcontinuous phase contains said cross-linked polymer at a concentrationranging between 10 and 25 mg/g.
 7. The composition according to claim 2,wherein the hydrogel constituting said continuous phase contains saidcross-linked polymer at a concentration ranging between 15 and 25 mg/g.8. The composition according to claim 2, wherein said polymer of saidhydrogel is produced by bacteria.
 9. The composition according to claim1, wherein said particles of said dispersed phase have a largestdimension ranging between 10 and 120 μm.
 10. The composition accordingto claim 1, wherein said particles of said dispersed phase have alargest dimension ranging between 20 and 80 μm .
 11. The compositionaccording to claim 1, wherein said particles of said dispersed phase arefragments having a rough surface obtained by crushing a mass ofhydrogel.
 12. The composition according to claim 1, wherein saidparticles of said dispersed phase have a water content, at equilibrium,ranging between 10 and 40% by weight.
 13. The composition according toclaim 1, wherein said particles of said dispersed phase have a watercontent, at equilibrium, of about 25% by weight.
 14. The compositionaccording to claim 1, wherein said dispersed phase consists of hydrogelparticles of a cross-linked copolymer of hydroxyethyl methacrylate(HEMA) and of ethyl methacrylate (EMA).
 15. The composition according toclaim 14, wherein said cross-linked copolymer contains the repeatingHEMA and EMA units in a ratio ${R = \frac{HEMA}{EMA}};$

said ratio R being included between 3.0 and 6.1.
 16. The compositionaccording to claim 15, wherein said ratio R is included between 3.5 and5.
 17. The composition according to claim 15, wherein said ratio is 4.1.18. The composition according to claim 14, wherein said cross-linkedcopolymer is obtained by reaction, for 100 parts by weight of monomers:HEMA+EMA, of: 77.5 to 87.5 parts by weight of HEMA, and 12.5 to 22.5parts by weight of EMA; in the presence of an efficient quantity of atleast one cross-linking agent.
 19. The composition according to claim14, wherein said cross-linked copolymer is obtained by reaction, for 100parts by weight of monomers: HEMA+EMA, of: 80 to 85 parts by weight ofHEMA, and 15 to 20 parts by weight of EMA; in the presence of anefficient quantity of at least one cross-linking agent.
 20. Thecomposition according to claim 1, wherein it contains from 10 to 30% bymass of said particles in suspension in said continuous phase.
 21. Thecomposition according to claim 1, wherein it contains from 15 to 25% bymass of said particles in suspension in said continuous phase.
 22. Amethod for preparing a composition according to claim 1, comprising: a.cross-linking an aqueous solution of at least one polymer selected fromproteins, polysaccharides and their derivatives to obtain the continuousphase; b. obtaining particles of at least one hydrogel resulting fromthe polymerization and cross-linking of acrylic acid, methacrylic acidand/or one derivative of said acids; c. optionally drying the saidparticles; and d. incorporating and mixing the said particles in saidcontinuous phase.
 23. The method according to claim 22, wherein the saidparticles are obtained by mechanically crushing a mass of the hydrogel.24. A method of reparative surgery or plastic surgery, comprising usingthe biocompatible diphasic composition according to claim 1 as a fillingmaterial.